RS-4252 inhibits amyloid beta-induced cytotoxicity in HeLa cells

Pharmacol Toxicol. 2003 Jul;93(1):29-32. doi: 10.1034/j.1600-0773.2003.930104.x.

Abstract

Progressive deposition of amyloid beta peptide in the senile plaques is a principal event in the neurodegenerative process of Alzheimer's disease. Several reports have demonstrated that amyloid beta is cytotoxic using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) as an indicator of viability in cells. With the MTT assay, we screened an in-house library to find compounds which suppress amyloid beta-induced inhibition of MTT reduction. We have previously reported that 6-ethyl-N,N'-bis(3-hydroxyphenyl)[1,3,5]triazine-2,4-diamine (named RS-0466), found in an in-house library, was capable of significantly inhibiting amyloid beta-induced cytotoxicity in HeLa cells. From further screening hits, we newly focused on 4-(7-hydroxy-2,2,4-trimethyl-chroman-4-yl)benzene-1,3-diol (named RS-4252), which show comparable potency to RS-0466 to ameliorate amyloid beta-induced cytotoxicity. Furthermore, RS-4252 reversed the decrease in phosphorylated Akt by amyloid beta. These results imply that RS-4252 or one of its derivatives has the potential to be a therapeutic for Alzheimer's disease patients, and that activation of Akt is at least in part involved in the effect.

Publication types

  • Comparative Study

MeSH terms

  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / toxicity
  • Chromans / pharmacology*
  • HeLa Cells
  • Humans
  • Oxidation-Reduction
  • Peptide Fragments / toxicity
  • Phenols / pharmacology*
  • Phosphorylation
  • Protein Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Tetrazolium Salts / analysis
  • Thiazoles / analysis
  • Triazines / pharmacology

Substances

  • 4-(7-hydroxy-2,2,4-trimethyl-chroman-4-yl)benzene-1,3-diol
  • 6-ethyl-N,N'-bis(3-hydroxyphenyl)(1,3,5)triazine-2,4-diamine
  • Amyloid beta-Peptides
  • Chromans
  • Peptide Fragments
  • Phenols
  • Proto-Oncogene Proteins
  • Tetrazolium Salts
  • Thiazoles
  • Triazines
  • amyloid beta-protein (1-40)
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • thiazolyl blue